This invention relates to sterilant compositions. More particularly, the invention relates to sterilant compositions with improved biocompatibility which may be employed in a wide variety of industrial processes where cleansing and/or sterilization of materials and apparatus are required, but which are particularly useful in the fields of medicine, food processing and wine making, where semi-permeable membranes are used. In these latter respects, compositions of this invention are eminently useful in the field of medicine, and especially that area thereof involving hemodialysis and the cleansing and sterilization of hemodialysis apparatus for reuse. Therefore, while the compositions of this invention are useful in a wide variety of areas, they are treated herein, in the interests of simplicity, in their application to the cleansing and sterilization of hemodialysis apparatus for reuse, although it is to be understood that this invention is not to be so limited.
The cleansing and sterilization of hemodialysis apparatus for reuse presents a number of problems. Initially, when the apparatus is employed to dialyze a patient, a degree of biocompatibility is established between the patient and the apparatus. For example, in a hemodialysis operation, first saline and then blood flows through the hollow fibers of the membrane of the dialysis apparatus while dialysate flows past the outside of the membrane fibers. At the commencement of the operation, the membrane is essentially in equilibrium with saline flowing through the fibers thereof and with dialysate on the other side. When blood is introduced into the system a new equilibrium relationship between fluids passing through the system and the membrane must be established. This new membrane equilibrium is completely different from the initial equilibrium established with the saline and the dialysate.
Generally, a membrane is in equilibrium with its environment when it has reached a state of ionic configuration, physical configuration, osmotic pressure, concentration gradients and hydronium ion gradients with the fluids which surround it. However, during the hemodialysis procedure the system never truly reaches an equilibrium state, but rather a quasi-steady state in which the composition of the inlet and outlet dialysate and blood changes only incrementally and only as a result of the dialysis process itself. Now, it is known that as a fluid, such as blood, containing dissolved or suspended particulates flows over a surface, such as the internal surfaces of the fibers of a hollow fiber membrane, constituents of the blood and dialysate are adsorbed on the surfaces of the device in accordance with individual entity relative absorbtion or reaction forces. Consequently, a rolling "front" of non-adsorbed or less strongly adsorbed materials and/or reaction products forms and proceeds as a concentrated mass towards the exit of the membrane system. While this is taking place, molecules and any sufficiently small particles pass through the membrane driven by differential concentration forces and enter the dialysis fluid. In a similar manner, entities contained in the dialysate may move from the dialysate into the blood stream. Once the surface quasi-steady state is established, the latter two activities are the main concerns of the dialysis operation.
Now, as the above mentioned activities take place, a complex protein layer consisting of general proteins such as albumen, fibrinogen, and other non-immunological macromolecules, from the circulating blood, plus immunological proteins, such as complement, are laid down on the internal surfaces of the membrane fibers. The presence of this deposited protein layer improves the biocompatibility between a patient undergoing hemodialysis and the dialysis system per se by isolating the flowing blood from the possible antigens on the surfaces of the hemodialysis device. This protein layer must be treated gently, since the improved biocompatibility exhibited thereby during reuse is a direct result of the protein layer per se. It must be kept in mind, however, that the dialysis membrane and the deposited protein layer are two separate entities, although, on second and subsequent usages they act as a system. The less the disruption of the protein layer, the greater the improvement in biocompatibility on subsequent use.
Reuse operations require that the kidney device be cleaned and disinfected. Cleaning is necessary to prevent build up of debris that would block the hollow fibers of the membrane and close the pores. Moreover, disinfection must be adequate to eliminate all spores, bacteria, viruses and fungi that may be introduced under any reasonable conditions. However, at the same time, it is necessary to conserve a high degree of biocompatibility of the system by employing reagents which minimize disturbance of the protein layer which has been laid down, thus conserving the improved biocompatibility which has been developed between the dialysis system and the patient upon reuse of the dialysis apparatus.
A known cleansing and disinfecting reagent used for cleaning and disinfecting dialyzing apparatus is formaldehyde. Formaldehyde is strongly adsorbed on the protein layer/membrane system. Formaldehyde reacts with protein in what is termed a tanning action. The use of formaldehyde has been associated with several adverse effects, such as carcinogenicity, acute hemolytic anemia, and auto-immune anemia associated with the development of anti-N-like red blood cell antibodies. Cleansers and disinfectants as used in common practice, such as a hydrogen peroxide and a product known as Chlorox (Registered TradeMark of The Chlorox Company, Oakland, Ca.) do not have these toxic effects. However, they disrupt the adsorbed protein layer.
The use of cleaning reagents, sterilants and disinfectants and the like is known in a wide variety of fields in order to cleanse, preserve and prevent deterioration or adverse effects from taking place in a given environment. However, many of the known materials of this type cannot be usefully employed in hemodialysis systems, since they might not only be destructive to the membrane and the protein layer laid down upon dialysis but also, since they might have further adverse biological effects, being incompatible with human physiology for other reasons, such as, for example, pH, acute toxicity, or mutagenicity.
At the same time that a cleansing and sterilant reagent suitable for use in hemodialysis systems which are to be reused preferably must not adversely effect or destroy the biocompatibility established by the protein layer deposited on the internal surface of the membrane fibers, such a cleansing and sterilant reagent must also provide the required cidal action. Cidal capacity is influenced by several factors, including, for example: (1) At equal sterilant concentrations, cidal action varies markedly as pH varies; (2) At equal pH, cidal action varies markedly with sterilant concentration; (3) At equal pH and/or sterilant concentration, cidal action varies markedly with time of contact of various organisms with the sterilant system; (4) Cidal action of any given sterilant or system containing the same decreases as decomposition reactions occur, thus decreasing the concentration of the sterilant available in such systems; and (5) In order to facilitate contact of cidal agent and microorganisms, the presence of surface active agents, that is, detergents, may in some cases not only be desirable, but actually required in order to facilitate contact between the cidal agents and the microorganisms present. In the latter respect, it is to be noted that a given degree of cidal action is accomplished more rapidly and at lower sterilant agent concentrations when such surface active agents are utilized. However, the use of such agents may also adversely affect the biocompatibility of the system. In cases where such detergent materials are not present, it is, in some situations, necessary to provide a physical means of contact between the cidal agent and the organisms present. The use of such detergent materials or physical means to facilitate contact between the cidal agent and the organisms present in the system adds further complexities to the system.
Dialyzer membranes are sensitive to variations in pH. Any significant excursion from a neutral pH of about 7 causes significant deterioration in the physical strength of the membranes. Many of the commercial sterilants currently used operate at highly acidic (pH less than about 5) or highly basic (pH greater than about 9) levels. This weakens the membranes; the weakening evidences itself clinically as an increase in blood leaks and in the laboratory as a decrease in burst pressure, as dealt with more fully below.
U.S. Pat. No. 4,084,747 discloses a germ killing composition produced by contacting an acid material, preferably which consists of at least about 15 percent by weight of lactic acid with sodium chlorite in aqueous media. The amount of acid in the composition must be sufficient to lower the pH of the aqueous media to less than about 7. The Patent also discloses methods of disinfecting and sanitizing, including application of either the germ killing composition per se, or the reactants which form the same, to provide in situ production thereof, to a germ carrier including substrates of various kinds as well as an enclosed air space.
U.S. Pat. No. 4,330,531 discloses a germ killing gel, a germ killing soap, a germ killing toothpaste and applicators for dispensing such germ killing compositions. The compositions include a first gel material containing sodium chlorite and a second gel material containing lactic acid in an amount sufficient to lower the pH of the aqueous media included therewith to less than about 7.
In contrast, U.S. Pat. No. 3,912,450 discloses a method for disinfecting or sterilizing medical, surgical and dental instruments or other objects with improved sporicidal compositions in liquid phase. The method is based upon the synergistic effects observed when combining non-ionic and anionic surfactants with aqueous or alcoholic glutaraldehyde solutions. The method can also be employed with ultrasonic irradiation over a wide frequency range.
U.S. Pat. No. 4,411,866 discloses an artificial organ assembly having an artificial organ with a built-in body fluid treatment mechanism, as well as a body fluid inlet port and a body fluid outlet port, filled with a liquid harmless to the human body an sealed. The assembly also includes an extracorporeal body fluid circulation mechanism which comprises a body fluid inlet line connected the the body fluid inlet port, filled with a liquid harmless to the human body and sealed. The whole assembly is hermetically vacuum-packaged and steam sterilized in a packaged state. The artificial organ assemblies include blood dialysis apparatus.
U.S. Pat. No. 3,124,506 discloses compositions of matter comprising malic acid and certain salts thereof which, when employed in a dentifrice, as a prophylactic composition for washing the nasal cavities, as a pargle, or in a perspiration odor inhibiting composition, improves the effectiveness of these various compositions for their intended purpose. As a dentifrice, the compositions are effective as tartar removing agents, antienzyme and sanitizer agents. As a nasal wash or gargle, the compositions aid in mobilizing and removing tenacious phlegm deposits from mucous linings of the mouth, nose and throat and exert a germicidal action. When employed as a deodorant, the compositions alleviate unpleasant perspiration odor and reduce perspiration.
U.S. Pat. No. 4,473,591 discloses the retention of the natural color of canned green vegetables by blanching the vegetables prior to packing in an aqueous solution of a metal ion selected from zinc and copper, the pH of the brine solutions ranging from 5.1 to 6.4.
U.S. Pat. No. 2,988,514 discloses an aqueous acidic bleaching bath having an acid pH of 1 to 7 which consists of water, a water-soluble metal chlorite selected from alkali metal chlorites and alkaline earth metal chlorites, and at least one of certain polyamines to prevent evolution of chlorine dioxide gas.
U.S. Pat. No. 3,585,147 discloses aqueous solutions containing stabilized chlorine dioxide gas dissolved therein in the form of an alkali metal chlorite at a pH between about 7 and 13 and adapted to release chlorine dioxide upon acidification to a pH of less than about 6 and having present therein a chloride of a metal selected from alkali metal and alkaline earth metals in an amount sufficient to increase the release of chlorine dioxide from the solutions.
Finally, U.S. Pat. No. 2,071,091 discloses the formation of chlorine dioxide solutions by acidification of chlorites of alkali and alkaline earth metals.
The present invention, in contrast to the above-mentioned patents, which neither recognize the problem or the need for biocompatible sterilant compositions of this type, provides suitable, biocompatible sterilant compositions which may be used in a wide variety of industrial processes where cleansing and/or sterilization are required and which are particularly useful in the reuse of hemodialysis equipment.